This application is a 371 of PCT/EP00/08421 filed Aug. 29, 2002.
The present invention relates a pharmaceutical formulation with increased solubility containing benzamide derivative or a pharmaceutically acceptable salt thereof, which are useful as drugs, and especially anticancer drugs. In particular, it relates to a pharmaceutical formulation containing high concentration of active ingredient with improved oral absorptivity, that may also be used as injection.
The benzamide derivatives used for the invention and their pharmaceutically acceptable salts have histone deacetylase inhibitory action, and are useful as therapeutic and/or ameliorating agents for disease connected with cellular growth, as effect enhancers for gene therapy, and as immunosuppressants. They exhibit particularly powerful effects as anticancer agents, and are effective for hematopoietic tissue tumors and solid tumors (Japanese Unexamined Patent Publication HEI No. 10-152462).
However, while the benzamide derivatives used for the invention have very satisfactory absorptivity when orally administered to mice and rats, some cases of low absorptivity have been found in dogs. Some cases of low absorptivity with oral administration have also been found even when the formulations are prepared using common additives such as lactose, corn starch, carboxymethyl cellulose, light anhydrous silicic acid, magnesium aluminometasilicate, magnesium stearate and titanium oxide. It has therefore been considered difficult to achieve stable blood concentration only with formulation for oral administration containing benzamide derivative or salt thereof as an active ingredient.
It has also been attempted to dissolve benzamide derivatives or their pharmaceutically acceptable salts in water, phosphate buffer solution and the like to make liquid drugs or injections, but their low solubility has made it impossible to obtain formulations of sufficient concentration.
Thus, injections containing benzamide derivatives or their salts as active ingredients must have very large volumes because of the poor solubility of the active ingredients, and it has therefore been difficult to provide them as drugs.
It is an object of the present invention to provide formulations with increased solubility and improved oral absorptivity for benzamide derivatives and their pharmaceutically acceptable salts that are useful as histone deacetylase inhibitors, and to provide injections containing the active ingredient at high concentration.
In order to overcome the problems described above, the present inventors have conducted diligent research on addition of various additives to benzamide derivatives and their pharmaceutically acceptable salts to improve solubility and absorptivity, and as a result the present inventors have completed the present invention upon finding that this object can be achieved by using certain types of additives.
In other words, the present invention provides:
[1] A pharmaceutical formulation comprising a benzamide derivative represented by formula (1): 
wherein A represents a structure represented by any one of the following in formula (2): 
or a pharmaceutically acceptable salt thereof, and one or more than one selected from the group consisting of surfactants, acidic substances, organic solvents and polyethylene glycols;
[2] The pharmaceutical formulation according to [1] further comprising water;
[3] The pharmaceutical formulation according to [1] or [2] wherein the benzamide derivative is represented by formula (3): 
[4] The pharmaceutical formulation according to any one of [1] to [3] wherein the surfactant is one or two selected from anionic surfactants and nonionic surfactants;
[5] The pharmaceutical formulation according to any one of [1] to [4] wherein the acidic substance is one or more than one selected from the group consisting of mineral acids, carboxylic acids, sulfonic acids, acidic polysaccharides, acidic amino acids, and salts of an amino acid and a mineral acid;
[6] The pharmaceutical formulation according to any one of [1] to [5] wherein the organic solvent is one or more than one selected from the group consisting of methanol, ethanol, propylene glycol, glycerin, propylene carbonate and dimethylacetamide;
[7] The pharmaceutical formulation according to any one of [1] to [6] wherein the molecular weight of the polyethylene glycol is from 200 to 20,000;
[8] The pharmaceutical formulation according to any one of [4] to [7] wherein the anionic surfactant is sodium lauryl sulfate;
[9] The pharmaceutical formulation according to any one of [4] to [8] wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester or a sugar ester;
[10] The pharmaceutical formulation according to [9] wherein the polyethylene sorbitan fatty acid ester is polysorbate 80;
[11] The pharmaceutical formulation according to [9] wherein the sugar ester is a sucrose ester of fatty acid;
[12] The pharmaceutical formulation according to any one of [5] to [11] wherein the mineral acid is hydrochloric acid, sulfuric acid or phosphoric acid;
[13] The pharmaceutical formulation according to any one of [5] to [11] wherein the carboxylic acid is citric acid, fumaric acid, adipic acid, tartaric acid, malic acid or acetic acid;
[14] The pharmaceutical formulation according to any one of [5] to [11] wherein the sulfonic acid is aminoethylsulfonic acid;
[15] The pharmaceutical formulation according to any one of [5] to [11] wherein the acidic polysaccharide is alginic acid;
[16] The pharmaceutical formulation according to any one of [5] to [11] wherein the acidic amino acid is aspartic acid or glutamic acid;
[17] The pharmaceutical formulation according to any one of [5] to [11] wherein the salt of an amino acid and a mineral acid is glycine hydrochloride, aspartic acid hydrochloride or glutamic acid hydrochloride.